72-OR: Mechanisms of Prediabetes Remission in People with Weight Gain after Lifestyle Intervention

We showed that weight loss-induced prediabetes remission during lifestyle intervention (LI) is determined by increased insulin sensitivity and protects from future T2D development. The extent to which remission of prediabetes occurs without weight loss, and if underlying mechanisms differ from weight loss-induced prediabetes remission, is unknown. In the Prediabetes Lifestyle Intervention Study (PLIS), people with prediabetes underwent a 12 months LI (dietary counselling and advice to increase physical activity) with metabolic assessments before and after, including 5-point OGTT, whole body MRI for fat distribution and ¹H-MRS for liver fat. Insulin sensitivity and secretion were assessed by OGTT-derived indices. Remission was achieved when fasting, 2h glucose and HbA1c normalized after LI (= responders (R), otherwise non-responders (NR)) according to ADA criteria. Of 1105 PLIS participants, 234 did not lose or gained weight during LI (median weight change: +2.1% IQR: 0.9 - 3.8), 51 were responders and 183 non-responders (22% remission rate). There were no between-group differences in change of body mass index (mean for R: 29.6±7.3 kg/m² to 30.6±7.5, for NR: 30.5±5.8 to 31.3±6.1, p group over time =0.47), whole body fat (R: 29.9±13.5 l to 32.0±14.3, NR: 30.6±12.0 to 32.1±12.8, p=0.92) or liver fat (R: 4.1±1.3% to 4.7±1.5, NR: 8.3±1.4 to 8.7±1.5, p=0.82). R had a stronger improvement in insulin sensitivity (OGIS, β₀ (95% CI): 28.3 (12.7-44.0), p=0.0016) and insulin secretion (AUC_c-pep0-30/AUC_gluc0-30, β₀ 11.3 (1.6-22.8), p=0.039). We replicated this in participants of the US Diabetes Prevention Program. R had a relative risk reduction of 71% to develop T2D than NR at 5 years after LI (risk ratio: 0.29, 95% CI 0.09-0.91, p=0.02). LI-induced prediabetes remission is possible in a substantial proportion despite weight gain and is similarly protective for T2D as weight loss remission. Underlying mechanisms include increased insulin secretion, in contrast to weight loss induced remission.